1Poxvirus and Rabies Branch, Division of High-Consequence
Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for
Disease Control and Prevention, Atlanta, Georgia
2Epidemic Intelligence Service, Scientific Education and
Professional Development Program Office, Centers for Disease Control and Prevention, Atlanta,
Georgia
3Office of Blood, Organ, and Other Tissue Safety, Division of
Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers
for Disease Control and Prevention, Atlanta, Georgia
4Maryland Department of Health and Mental Hygiene,
Baltimore
5Infectious Diseases Pathology Branch, Division of
High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious
Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
6Veterans Affairs Medical Center, Washington, DC
7George Washington University School of Medicine, Washington,
DC
8North Carolina Division of Public Health, Raleigh
9University of Miami Miller School of Medicine–Miami
Transplant Institute, Miami, Florida
10Northwestern University Feinberg School of Medicine,
Chicago, Illinois
11Walter Reed National Military Medical Center, Bethesda,
Maryland
12Emory University School of Medicine, Atlanta,
Georgia

ABSTRACT

ImportanceThe rabies virus causes a fatal encephalitis and can be transmitted through tissue or organ
transplantation. In February 2013, a kidney recipient with no reported exposures to potentially
rabid animals died from rabies 18 months after transplantation.

ObjectivesTo investigate whether organ transplantation was the source of rabies virus exposure in the
kidney recipient, and to evaluate for and prevent rabies in other transplant recipients from the
same donor.

DesignOrgan donor and all transplant recipient medical records were reviewed. Laboratory tests to
detect rabies virus–specific binding antibodies, rabies virus neutralizing antibodies, and
rabies virus antigens were conducted on available specimens, including serum, cerebrospinal fluid,
and tissues from the donor and the recipients. Viral ribonucleic acid was extracted from tissues and
amplified for nucleoprotein gene sequencing for phylogenetic comparisons.

Main Outcomes and MeasuresDetermination of whether the donor died from undiagnosed rabies and whether other organ
recipients developed rabies.

ResultsIn retrospect, the donor’s clinical presentation (which began with vomiting and upper
extremity paresthesias and progressed to fever, seizures, dysphagia, autonomic dysfunction, and
brain death) was consistent with rabies. Rabies virus antigen was detected in archived autopsy brain
tissue collected from the donor. The rabies viruses infecting the donor and the deceased kidney
recipient were consistent with the raccoon rabies virus variant and were more than 99.9% identical
across the entire N gene (1349/1350 nucleotides), thus confirming organ
transplantation as the route of transmission. The 3 other organ recipients remained asymptomatic,
with rabies virus neutralizing antibodies detected in their serum after completion of postexposure
prophylaxis (range, 0.3-40.8 IU/mL).

Conclusions and RelevanceUnlike the 2 previous clusters of rabies virus transmission through solid organ transplantation,
there was a long incubation period in the recipient who developed rabies, and survival of 3 other
recipients without pretransplant rabies vaccination. Rabies should be considered in patients with
acute progressive encephalitis of unexplained etiology, especially for potential organ donors. A
standard evaluation of potential donors who meet screening criteria for infectious encephalitis
should be considered, and risks and benefits for recipients of organs from these donors should be
evaluated.

Figures in this Article

Rabies is a fatal, acute progressive encephalitis caused by neurotropic zoonotic viruses
belonging to the genus Lyssavirus.1 Unique
rabies virus variants, distinguishable by molecular typing methods, are associated with specific
animal reservoirs. Globally, an estimated 55 000 persons die of rabies every year, with most
transmission attributable to dog bites.2 Approximately 2
human rabies deaths are reported in the United States every year, and during 2000 through 2010, all
but 2 domestically acquired cases were associated with bats.3- 5 Despite raccoons being the most frequently reported
rabid animal in the United States, only 1 human rabies case associated with the raccoon rabies virus
variant has been reported.3,5

Rabies virus transmission has occurred through tissue and solid organ transplantation.6- 8 In the 2 previously recognized clusters
of rabies virus transmission through organ transplantation, which were attributed to a bat and a
canine rabies virus variant, all recipients except 1 who was previously vaccinated had rabies
symptom onset within 6 weeks of transplantation and died.6,7 These observations suggest a high infectivity rate and an incubation
period of approximately 6 weeks in unvaccinated immunosuppressed recipients of solid organs from
donors with rabies.

In February 2013, a patient died of rabies 18 months after receiving a deceased-donor kidney
transplant. The Centers for Disease Control and Prevention (CDC) and state and local health
departments conducted an investigation to determine whether rabies virus was transmitted through
transplantation and to prevent rabies in other recipients and contacts.

CASE REPORT (DECEASED KIDNEY RECIPIENT)

In February 2013, a man who received a deceased-donor kidney transplant in September 2011
presented to an emergency department (ED) complaining of right hip pain with radiation to the lower
extremity (Figure 1). He was diagnosed with sciatica
and discharged but was admitted 4 days later with fever, diaphoresis, nausea, right lower extremity
weakness, and right lower abdominal pain near the site of his transplanted kidney. His symptoms
progressed to bilateral lower extremity weakness with ascending paresthesias. He developed
encephalopathy, excessive salivation, and hemodynamic instability and died 22 days after
admission.

Place holder to copy figure label and caption

Figure 1.

Clinical Course of the Transplant Recipients Who Received Solid Organs From a Donor With
Rabies

METHODS

This activity was reviewed according to CDC National Center for Emerging and Zoonotic Infectious
Diseases institutional procedures. It was deemed to not constitute human subjects research and was
therefore not subject to institutional review board requirements.

Clinical and Epidemiologic Review

To determine whether the deceased kidney recipient acquired rabies virus infection through
transplantation and to identify other potentially infected recipients from the same donor, medical
records of the donor and recipients were reviewed. Interviews with family members of the deceased
kidney recipient and donor were conducted.

Laboratory Specimen Collection and Testing

Laboratory testing was conducted at CDC. Antemortem rabies testing of the deceased kidney
recipient was performed on serum, CSF, nuchal skin biopsy, and saliva specimens. After the kidney
recipient’s death, additional tests were conducted on urine and transplanted kidney biopsy
specimens collected during hospitalization and on tissues collected during autopsy. Donor specimens
were obtained from storage, including serum and oral cavity biopsy tissue collected during unrelated
dental surgery and tissues collected during autopsy. Specimens from the other recipients were also
tested.

Serum and CSF were analyzed for rabies virus–specific binding IgG and IgM antibodies using
the indirect fluorescent antibody test and for RVNAs using the rapid fluorescent focus inhibition
test.9,10 The direct fluorescent antibody test was
used to detect rabies virus antigen in nuchal skin biopsy.9,10 Tissue specimens were examined using hematoxylin-eosin stains or
immunohistochemical (IHC) stains with mouse or
rabbit hyperimmune rabies virus antiserums.5,7,11,12 Ribonucleic acid was extracted and
amplified from saliva, urine, and tissues by heminested reverse transcriptase–polymerase chain
reaction (RT-PCR) targeting the rabies virus
nucleoprotein (N) gene.10 Polymerase chain
reaction products of the expected molecular weight were sequenced. Phylogenetic analysis was
performed (Molecular Evolutionary Genetics Analysis version 5.0; Biodesign Institute) by comparing
these sequences to those available in GenBank and to those of rabies viruses circulating within
raccoon populations in the eastern United States that were newly sequenced for this
investigation.10,13

RESULTS

Organ Donor

In August 2011, a previously healthy man presented to a primary care clinic after returning from
a fishing trip with nausea, vomiting, and upper extremity paresthesias on each of 4 consecutive
days. He was transported to an ED where he was febrile and had peripheral leukocytosis (white blood
cells, 24 800/μL), hyponatremia (sodium, 128 mEq/L), and hypokalemia (potassium, 2.0
mEq/L). Shortly after arrival to the ED, he had a seizure and was admitted. While hospitalized, he
had dysphagia to liquids and altered mental status requiring intubation. He experienced autonomic
dysfunction with hypothermia and hemodynamic instability. The patient was declared brain dead 17
days after symptom onset with a presumed diagnosis of ciguatera poisoning.

Cerebrospinal fluid analysis performed during the initial ED evaluation revealed a pleocytosis
(white blood cells, 9/μL). Tests for HIV, cytomegalovirus, varicella-zoster virus, herpes
simplex virus, and Cryptococcus had negative results, but Epstein-Barr
virus–specific serum IgG antibodies were detected. No abnormalities were noted on brain MRI.
Organ donor eligibility screening was conducted; the questionnaire administered to family members
included an item assessing exposure to potentially rabid animals or receipt of rabies postexposure
prophylaxis (PEP) due to suspected exposure within
the previous 6 months. No increased risk for infectious disease transmission was identified, and
kidneys, heart, and liver were transplanted into 4 recipients. No vessels or tissues were
transplanted.

Independent of organ procurement, an autopsy was performed, and tests for various arboviruses,
enteroviruses, coronaviruses, adenoviruses, influenza viruses, parainfluenza viruses, and human
metapneumovirus had negative results. The brain was soft and friable with blurring of the gray-white
matter junction reflecting gross and histologic changes consistent with prolonged ventilator-induced
effect. At the time of autopsy, histopathologic features to suggest a definitive diagnosis were not
observed on examination of brain tissue. As part of the autopsy-related investigation, local water
temperature evaluation determined the presence of ciguatoxin to be extremely unlikely. The cause of
death was ultimately attributed to complications of severe gastroenteritis.

Although the organ procurement organization screening questionnaire queried exposure to
potentially rabid animals in the last 6 months, subsequent interviews with family members conducted
during the epidemiologic investigation revealed that the donor had significant wildlife exposure,
such as hunting and trapping animals in North Carolina. Activities specific to raccoons included
trapping and keeping them in captivity, using them as live bait during dog training exercises, and
preparing pelts for display. Through these activities, the donor sustained at least 2 raccoon bites,
18 and 7 months prior to symptom onset, for which he did not seek medical care. The captive raccoon
responsible for the latter bite was healthy up to 4 weeks after the bite. Neither raccoon was
available for testing.

Other Transplant Recipients

The 3 other recipients (right kidney, heart, and liver) did not have signs or symptoms consistent
with rabies or encephalitis. All received PEP with rabies immune globulin and 5 doses of rabies
vaccine, and remain asymptomatic.14,15
Immunosuppressive regimens are summarized in Figure 1.
The heart recipient experienced mild graft rejection. Other posttransplantation complications
included BK virus–associated nephropathy in the asymptomatic kidney recipient and herpes
zoster in the liver recipient.

Laboratory Findings

For the deceased kidney recipient, rabies virus–specific binding IgG and IgM antibodies and
RVNAs were detected in serum collected during his illness but were not found in CSF (Table). Diffuse and extensive encephalomyelitis and rare
intracytoplasmic inclusions typical of rabies were observed in central nervous system (CNS) tissues
following hematoxylin-eosin staining (Figure 2).
Abundant rabies virus antigens were also detected by IHC staining in examined CNS tissues but not
the transplanted kidney. Rabies virus RNA was detected in saliva, nuchal skin biopsy, and postmortem
CNS tissues but not the transplanted kidney.

For the organ donor, rabies virus–specific binding IgG and IgM antibodies and RVNAs were
retrospectively detected in serum collected during his illness (Table). Nonsuppurative encephalitis and widespread neuronal necrosis were
observed in archived CNS tissues after hematoxylin-eosin staining (Figure 2). Numerous intracytoplasmic inclusions typical of rabies were
evident within cortical neurons and Purkinje cells. Rabies virus antigen was detected by IHC
staining in all examined brain sections and in gastric and colonic ganglia. Rabies virus RNA was
detected in postmortem CNS tissues.

Sequence analysis of PCR products generated from the deceased kidney recipient and donor were
more than 99.9% identical across the entire N gene (1349/1350 nucleotides) and were
consistent with the raccoon rabies virus variant. Given the known variability of the
N gene between different rabies virus variants (up to 20%) and between distinct
raccoon rabies virus variant clades (3%), phylogenetic analysis was able to identify independent
raccoon rabies foci with a geographic resolution to the county level. The deceased kidney recipient
and donor rabies virus N gene sequences formed a separate clade (Figure 3) and matched each other closer than any other
raccoon rabies virus variant N gene, confirming organ transplantation as the route
of transmission.13

Place holder to copy figure label and caption

Figure 3.

Phylogenetic Reconstruction of the Rabies Viruses Infecting the Deceased Kidney Recipient and
Donor

The N gene sequences of the rabies viruses infecting the deceased kidney
recipient and donor are shown in relation to N gene sequences of common rabies
virus variants circulating in the United States. The phylogenetic reconstruction was generated with
the neighbor-joining method under the maximum composite likelihood model to estimate nucleotide
substitutions. The bootstrap method with 1000 iterations was used to assess the confidence of the
branching pattern (numbers at the nodes). Branches are color coded according to reservoir host, with
triangles representing collapsed branches with a common origin. The Duvenhage virus was used as an
outgroup to better visualize the evolutionary relationships among rabies virus clades. Independent
geographic foci associated with the raccoon rabies virus variant circulating in the eastern United
States, in black, are shown along with the corresponding state (2-letter abbreviations). Enclosed in
the rectangle on the left is a magnified projection showing the topology of the collapsed North
Carolina cluster, which includes sequences obtained from various rabid animals, the deceased kidney
recipient, and the donor.

For the 3 asymptomatic recipients, rabies virus–specific binding IgG and IgM antibodies and
RVNAs were not detected in serum collected immediately prior to PEP initiation. However, titers of
RVNAs suggesting an appropriate immune response were detected in all 3 recipients after PEP
completion (Table).14,15 Rabies virus antigen and RNA were not detected in routine
postoperative transplanted organ biopsy specimens or in specimens obtained during an unrelated
posttransplant procedure.

DISCUSSION

This is the third reported transmission event of rabies virus through solid organ transplantation
and has a number of unique aspects. To our knowledge, this is the first report in which unvaccinated
recipients of solid organs from a donor with rabies did not all develop disease. The symptomatic
recipient’s incubation period is the longest documented in a transplant recipient who had not
received prior rabies vaccination.6- 8
In contrast, previous reports have noted universal transmission and fatality among unvaccinated
solid organ recipients.6,7

The deceased kidney recipient and donor described here were infected by the raccoon rabies virus
variant. This variant has been reported to infect only 1 other person previously.5 This transmission event provides an opportunity for enhancing
rabies awareness and recognition and highlights the need for a modified approach to organ donor
screening and recipient monitoring for infectious encephalitis. This investigation also underscores
the importance of collaboration between clinicians, epidemiologists, and laboratory scientists.
Identification of the geographic origins of the rabies viruses of the deceased kidney recipient and
donor through a phylogenetic approach complemented the information obtained during epidemiologic
investigations and was critical for confirming the role of transplantation in disease
transmission.

Since the 1970s, the raccoon rabies virus variant has spread across the eastern United
States,16,17 which is concerning as raccoons
increasingly inhabit urbanized areas.18 Nevertheless,
recognized human infections with the raccoon rabies virus variant are rare compared with those
associated with bat rabies virus variants.4,5 This
may be because bites from raccoons are usually more apparent compared with smaller bites such as
those from bats.19 Persons may therefore be more likely to
present for medical care and receive PEP after raccoon bites than bat bites, although the lack of
systematically collected data on animal bites or PEP usage makes this hypothesis difficult to
verify.14,19 The donor described reportedly
experienced raccoon bites but had not sought medical care and therefore did not receive PEP.
Administration of PEP is efficacious against rabies, and persons who come in contact with raccoons
should be evaluated for PEP.14,15 Based on his
frequent contact with potentially rabid animals, the donor may have also been a candidate for rabies
pre-exposure prophylaxis.14,15

Approximately one-third of domestic human rabies cases are diagnosed postmortem.9,20 More than 1000 persons die annually of unexplained
encephalitis in the United States.21 Because of the rarity
and lack of clinical and pathologic recognition of rabies, the disease may go undiagnosed.4,5 Diagnosis is further complicated by the variable
presentation of rabies.1,4,20 Initial
signs and symptoms are sometimes nonspecific, and clinicians may not elicit an exposure history if
they do not inquire about animal contacts and travel history.22,23 This report emphasizes the need for increased awareness among
clinicians and suggests that rabies should be considered in patients with unexplained, acute
progressive encephalitis.20,22 Timely diagnosis is
essential for prompt initiation of experimental treatment protocols, as there are rare reports of
rabies survivors.24,25 Recognition of rabies is
also important to identify persons who may need PEP.14,15

The deceased kidney recipient had an unexpectedly long incubation period, and the 3 other solid
organ recipients were unvaccinated but remained asymptomatic for an 18-month period between
transplantation and administration of PEP, in contrast to prior reports of rabies virus transmission
through transplantation.6,7 The typical rabies
virus incubation period is believed to be shortened among recipients of organs or tissues from
infected donors, especially when recipients are immunosuppressed.4,6,7,9 For example, the longest recorded incubation
period to our knowledge in an unvaccinated recipient after a cornea transplant, a procedure that
does not typically require immunosuppression, is 39 days.8
The deceased kidney recipient’s incubation period was approximately 13 times longer than this
despite both immunosuppression and solid organ transplantation. It is unclear whether the donor had
a similarly lengthy incubation period, as the precise exposure responsible for his infection is
unknown. Notably, the incubation in the only other reported human case of raccoon rabies virus
variant infection is also uncertain.5 The causes of the
prolonged incubation period of the deceased kidney recipient are unclear but could include exposure
to a low dose of virus or distinct characteristics of raccoon rabies virus variant pathogenesis in
humans.26,27

Rabies virus–specific binding antibodies and RVNAs were not detected in the serum of the 3
asymptomatic recipients prior to PEP initiation. All subsequently developed RVNAs after PEP was
initiated.28- 30 The asymptomatic
recipients could have been within the incubation period and might have developed clinical infection
had they not received PEP. These observations raise questions about mechanisms of rabies virus
spread within a host, the cells and tissues in which the virus resides during lengthy incubation
periods, and how the virus evades the immune system.31
Differences in the immunosuppressive induction and maintenance regimens among the recipients could
have also affected disease progression if these regimens resulted in varying degrees of
immunosuppression. The effect of immunosuppressive medications, along with inoculum dose, type of
transplanted organ, and host characteristics on rabies pathogenesis, is presently unclear.32,33

In addition to rabies, since 2002 there have been 11 other reported instances in the United
States in which infectious encephalitis was transmitted through solid organ transplantation,
including West Nile virus, lymphocytic choriomeningitis virus, and Balamuthia
mandrillaris.7,34- 39
Infectious encephalitis can have nonspecific clinical features easily mistaken for other disease
conditions, particularly in patients with multiple comorbidities such as organ transplant
recipients.40 Even if transplant-associated encephalitis is
suspected, establishing the diagnosis in donors or recipients requires that appropriate specimens be
collected, which may not be possible if autopsies have not been performed or archived tissue
specimens are unavailable. Specimen testing for the diagnosis of rare pathogens must often be
conducted by reference laboratories. Furthermore, organs recovered from a common donor are often
distributed to multiple, geographically dispersed transplant centers. Hence, encephalitis that
develops in one recipient may not be recognizable as transplant-associated without knowledge of the
clinical status of other recipients. To facilitate the identification of transplant-associated
infections, transplant centers are required to report potential donor-derived infections to the
Organ Procurement and Transplantation Network.

Currently, the rarity of rabies and time required to transfer samples and perform adequate
laboratory diagnostics for rabies makes universal screening of all organ donors impractical.
However, given the lethality of transplant-associated encephalitis, implementation of a standardized
approach for recognizing infectious encephalitis among organ donors is warranted. Prompt recognition
of infectious encephalitis allows for the initiation of prophylaxis, treatment, and appropriate
management of recipients. Presently, there is no standardized case definition of infectious
encephalitis among organ donors, although expert opinion for recognizing CNS infections in potential
organ donors is available.41 If infectious encephalitis is
suspected by clinicians treating a potential organ donor, organ procurement organizations are tasked
with appropriately communicating this information to transplant centers. In the present case, the
questionnaire routinely administered by the organ procurement organization to family members
included screening for potential rabies virus exposures but did not identify risk. Adoption of a
uniform donor questionnaire that more effectively elicits risk factors may improve the screening of
donors with encephalitis, but is unlikely to be sufficiently sensitive or specific compared with
laboratory testing.

Efforts to develop a standardized case definition for infectious encephalitis and to identify
clinical criteria that could be applied during the predonation screening process are necessary. Such
organs should be used only in extreme circumstances with careful risk-benefit assessment. When
criteria are met to suggest that a donor could have infectious encephalitis, a standardized approach
to specimen collection, storage, and appropriate laboratory testing could improve probability of
recognition. These might include performing a donor autopsy and archiving of CNS tissue and CSF in
addition to the current practice of archiving serum specimens. Additionally, efforts might include
identifying a panel of transplant-transmissible infections for which testing is recommended when a
donor meets criteria for infectious encephalitis.

Because of organ shortages and poor prognosis of patients on transplant waiting lists, the
clinical decision to proceed with transplant must be made quickly. Although test results may not be
available prior to transplantation, prompt notification to transplant centers of postmortem test
results could improve management among recipients. Currently, recipients must provide special
informed consent when an organ donor is deemed to be at increased risk for HIV, hepatitis B, or
hepatitis C infection.42 In addition to a thorough
risk-benefit assessment, special informed consent for receipt of an organ from a donor meeting
infectious encephalitis criteria should be considered at time of organ offer. The risk of adverse
events faced by recipients of organs from donors who could have infectious encephalitis is unknown.
Hence, there is a need to better understand the prevalence of infectious encephalitis among
donors.

In summary, rabies in the setting of solid organ transplantation can be transmitted variably and
may have a long incubation period. Although recognition of rabies is challenging and solid organ
transplant transmission of infectious encephalitis is rare, further education to increase awareness
is needed. Concerted efforts to improve screening of donors with suspected encephalitis, to
carefully consider risks and benefits of transplanting organs from these donors, and to better
monitor transplant recipients for rapid recognition of infection may improve patient management and
prevent further transmission.

Conflict of Interest Disclosures: All authors
have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and
none were reported.

Funding/Support: This investigation was supported
by the Centers for Disease Control and Prevention (CDC),
Maryland Department of Health and Mental Hygiene,
North Carolina Division of Public Health, and
Florida Department of Health and funded as part of
routine infectious disease outbreak investigation activities.

Role of Sponsor: The CDC, Maryland Department of Health and Mental Hygiene, North
Carolina Division of Public Health and Florida Department of Health employees had a role in the
design and conduct of the study; collection, management, analysis, and interpretation of the data;
preparation, review, or approval of the manuscript; and decision to submit the manuscript for
publication.

Disclaimer: The findings and conclusions in this report are those of the authors and
do not necessarily represent the official position of the CDC, Department of Army/Navy/Air Force,
Department of Defense, or US government.

Phylogenetic Reconstruction of the Rabies Viruses Infecting the Deceased Kidney Recipient and
Donor

The N gene sequences of the rabies viruses infecting the deceased kidney
recipient and donor are shown in relation to N gene sequences of common rabies
virus variants circulating in the United States. The phylogenetic reconstruction was generated with
the neighbor-joining method under the maximum composite likelihood model to estimate nucleotide
substitutions. The bootstrap method with 1000 iterations was used to assess the confidence of the
branching pattern (numbers at the nodes). Branches are color coded according to reservoir host, with
triangles representing collapsed branches with a common origin. The Duvenhage virus was used as an
outgroup to better visualize the evolutionary relationships among rabies virus clades. Independent
geographic foci associated with the raccoon rabies virus variant circulating in the eastern United
States, in black, are shown along with the corresponding state (2-letter abbreviations). Enclosed in
the rectangle on the left is a magnified projection showing the topology of the collapsed North
Carolina cluster, which includes sequences obtained from various rabid animals, the deceased kidney
recipient, and the donor.

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